Embryos Get More Than Just DNA From Dad

A team of researchers, including two at Utah State University, recently published their discovery of one possible mechanism that can explain how men pass along more information than just their DNA sequence to their offspring, and how that may cause developmental problems.

As embryos develop, early gene activity shapes the traits that offspring inherit from their parents. Consequently, changes in how information from a gene is used as an embryo develops (gene expression) are thought to change these traits, even when the DNA sequence inherited from the parents is not changed. But how these kind of changes? epigenetic changes? happen is not well understood.

Ralph Meyer, associate professor, and Mirella Meyer-Ficca, research assistant professor in Utah State University’s School of Veterinary Medicine are part of a team (see complete list of authors below) that has demonstrated that in sperm, the amount a group of proteins called histones, and importantly their distribution along the father’s DNA, affect how genes, particularly those related to early embryo development and cell signaling, are used in gene expression. Changes and errors in this “programming” of the father’s DNA alter how the offspring utilize the genes it inherited from the father, and this may be associated with developmental problems and disorders later in life. Their paper was published in PLOS Genetics, an online open-access, peer-reviewed journal.

Histones are proteins that are present in all cells of the body, and control the DNA packaging in those cells. In contrast, as sperm cells develop, they eliminate most histones in order to tightly and safely pack their DNA using another kind of protein that does not contain the “programming” properties of histones. Meyer explained that the team worked with a mouse model that allowed them to change the amount of histone that remained in the sperm, either using a genetically altered mouse, or by treating the male mice with an experimental anticancer drug. They confirmed a connection between sperm histones’ distribution and gene expression patterns in embryos that those male mice sired in unaltered control female mice.

Meyer said it is particularly interesting that epigenetic information that passes from a father to his offspring can change and adapt during his lifetime. What those changes may be, what affect they have on offspring, and how that happens are big questions Meyer and colleagues continue to explore. “This is only the beginning,” Meyer said. “Now we have to learn what could be some of the influencing factors.”

Passing on More than Genes: Is it Time for the Male Equivalent of Prenatal Vitamins?

When sperm retain different levels of histones, it is not a case of “all or none.” Instead, it appears that the responses to things in a male’s diet and environment have a gradual affect. “If we think this through it means there are acquired traits that are passed on to our offspring,” Meyer said. Not long ago such a statement would have been biological heresy. But in just the past few years, other scientists have found, for example, that fathers who are obese and diabetic are likely to have children who are obese and diabetic.

Meyer and others hope to discover what the pathways for passing along those epigenetic traits might be. One possible pathway that follows on the team’s histone research involves a process in cells that depends on how animals uptake or synthesize vitamin B3 (niacin, nicotinamide). Meyer said it is well-established that other vitamins, folate, for example, are important in fetal development. Humans cannot derive nicotinamide from protein the way that mice do, which is why many foods we eat are fortified with it. Because vitamins are so important for fetal development, pregnant women, and women who plan to become pregnant, are prescribed prenatal vitamins.

Meyer wonders if children might also benefit from fathers taking certain vitamins before they conceive a child. It’s a big question that will take a lot of time to answer, and just one of the many questions the research team is considering as they work to understand more about the intricacies of reproductive biology. The work Meyer and his colleagues do is primarily done in mice, as a model for how it works in humans.

Males and Miscarriages

“There are many couples who have problems conceiving,” Meyer said. “It is a very trying situation for them. A woman has a miscarriage and people think it is a health problem she has. According to what we see, if sperm are misprogrammed, this could also lead to miscarriages. We see it over and over again in our mice. We think it’s highly possible, based on data from our lab and data coming from others, that a miscarriage could also be because of him and not just because of her.”

Meyer said this finding also means we need better methods of testing males’ reproductive health. “We oftentimes just examine sperm and ask, ‘Does it look about right and wiggle?’ , and if it does we say it’s fine,” he said. “But in our study we compared sperm from other mice for size, shape, swimming and the only difference we can see from the outside is that they tend to be just slightly more round-shaped than normal sperm, and you need to be looking very rigorously to see the difference.”

The project had its beginnings actually in 1997 when Meyer and Meyer-Ficca were students and saw some interesting things in rats that they could not explain. It’s taken years for methods and other researchers’ discoveries to provide the tools and framework for sorting it out. The next steps will also take years, but they remain enthusiastic.

“Reproduction is the bottleneck of life for each species,” Meyer said. “The germ cells (the ova and sperm), are the special one cell from mom and the special one cell from dad that can form a new life. Once they come together, the embryo forms and for the first time starts its own gene expression. It’s the crucial step to pass on life from one generation to the next, passing along our germ cells. They are the ‘immortal’ piece of each species.”